Despite enormous expenditures and efforts by academic, government, and pharmaceutical institutions over many years, most breast cancer drugs that show promise in mice, fail to cure breast cancer in patients. Such inefficiency is enormously costly and hampers identification of new and effective breast cancer drugs. This discrepancy suggests that mice are not a reliable model for correct prediction of drug responsiveness of human breast cancer. Nonetheless, before candidate drugs against breast cancer are allowed into clinical trials, FDA requires promising effects on human breast cancer grown in immunodeficient mice. We have discovered and corrected a key hormonal deficiency of mice that make regular mice suboptimal for modeling and drug testing of estrogen receptor-positive human breast cancer. We have created genetically engineered mice that restore the missing hormone component, pituitary human prolactin, and have determined that the prolactin-humanized mice are excellent recipients for estrogen receptor-positive patient-derived breast cancer tissues. Intriguingly, two of the first estrogen receptor-positive patient derived lines tha we have established spontaneously metastasize to lungs from orthotopic mammary implantation sites. These models will for the first time allow us to explore new therapeutic strategies to improve the efficacy of anti-estrogens in the metastatic setting. This is important because adjuvant treatment for breast cancer is given after surgical resection of primary tumors, and breast cancer patients die from metastases and not from the primary tumor. The objectives will be achieved by exploring combination treatment of antiestrogens with prolactin-pathway suppressive drugs as well as parallel molecular profiling of lung metastases and primary tumors to identify alternative candidate drug targets. The novel concepts of this exploratory R21 project are supported by solid scientific rationale and previously unavailable experimental models. The potential impact is strong, with the possibility of uncovering improved therapeutic strategies to metastatic ER-positive breast cancer that could benefit patients within a very short time frame. This project is significant because the majority of patients who die from breast cancer were initially diagnosed with ER-positive disease. Finally, the new hormonally improved mouse model could benefit individual patients immediately by serving as a culture vessel to determine the sensitivity of a patient's tumor against a panel of existing drugs. Life-saving, tailored therapy fr metastatic breast cancer could be a result.